Adenosine is an autocoid produced in many tissues to mediate various functions through four receptor subtypes, A1, A2A, A2B and A3. All four receptors belong to the class of G-protein coupled receptors (GPCRs), which contain seven helical hydrophobic domains that span plasma membrane, connected by hydrophilic extracellular and intracellular loops. A1 and A3 receptors couple to Gi and Go proteins, while A2A and A2B receptors are coupled to Gs proteins. Because of these differences, adenosine signals an increase in intracellular cAMP levels via its action through A2A and A2B receptors, and a decrease through A1 and A3 receptors. In addition, adenosine increases intracellular calcium ion levels via A2B receptor, because of its coupling to Gq proteins.
The compounds of formula I have potent adenosine human A2B receptor antagonist activity as measured in CHO-A2B-cAMP assay. These compounds also have residual potent human A1 and human A2A antagonist activity, as measured in the radiolabeled ligand binding assays.
The study of role of A2B receptor's functional activity on various cell types was complicated by the absence of selective A2B agonists and antagonists vs other three receptors. Typically, the functional activity of A2B receptor is deduced by the absence of effects of the selective agonists and antagonists at other three adenosine receptors, while eliciting response with NECA, a potent and non-selective adenosine receptor agonist. Usually, the role of A2B receptor on a given cell type, is identified when the following unique order of agonist potency is observed; NECA (non-selective)>PIA (A1-selective agonist)>IB-MECA (A3-selective agonist)>CGS-21680 (A2A-selective agonist).
Adenosine's relative agonist potency against the four receptors was determined to be, A1 (EC50−0.31 uM)>A3 (EC50−0.29 uM)>A2A (EC50−0.7)>A2B (EC50 −24 uM), suggesting a unique role for A2B receptor during chronic, high oxidative stress conditions, including but not limited to hyperglycemia, mast-cell activation, and gastrointestinal tract inflammation. In spite of low agonist potency of adenosine to the A2B receptor, numerous compounds with high A2B receptor antagonist potency have been reported.
Using specific agonists and antagonists, Eisai researchers demonstrated the key role of A2B receptor antagonism in inhibiting hepatic glucose production, and a potent A2B receptor antagonist and an inhibitor of glucose production in rat primary hepatocytes was also shown to lower fasting and fed glucose levels in KK-Ay mice, a well recognized model of type 2 diabetes. Thus, compounds of present invention have utility in preventing and/or treating type 2 diabetes.
A2B receptors are also present in the plasma membranes of endothelial cells and have been found to stimulate their growth. Since this will lead to growth of new blood vessels (angiogenesis). An object of this invention is to prevent and/or treat diseases characterized by abnormal blood vessel growth, such as diabetic retinopathy.
Using immuno-fluorescence techniques with a specific anti-human A2B-antibody indicated the presence of A2B receptors in human lung mast cells obtained from asthmatics by bronchoalveolar lavage cells. Thus, the compound of formula I provide a method of preventing and/or treating asthma, bronchospastic and allergic diseases as well as other obstructive airway-type diseases.
A2B receptors are found in the colon in the basolateral domains of intestinal epithelial cells, and increases chloride ion secretion in reaction to the gastrointestinal tract inflammation in diseases such as, diarrhea. Thus, the compounds of formula I provide a method to treat inflammatory gastrointestinal tract disorders including diarrhea.
The compounds of present invention also have potent antagonist activity against A1 and A2A receptors, in addition to the A2B receptors. Hence, compounds of formula I provide methods to treat diseases where adenosine A1, A2A and A2B receptor antagonism plays a role, such as depression, Parkinsons disease, and hypertension.
Some substituted N-acyl aminothiazoles are known in the art, for example, indenothiazolyl phosphonates have been disclosed in U.S. Pat. No. 5,480,874; 2-amino-6-hydroxybenzothiazoles in U.S. Pat. No. 4,929,623; 2-benzoylaminonaphtho[1,2-d]thiazoles in Synthetic Communications (1993), 23(17), 2347-53; benzamido- and 2-acetamidobenzothiazole derivatives in Indian Drugs, (1985), 23(3), 146-51 and certain acylaminothiazole derivatives in U.S. Pat. No. 5,189,049. In U.S. Pat. No. 4,877,876 there are disclosed 2-substituted-8H-indeno(1,2-d)-thiazole derivatives which are similar to the presently claimed compounds.